Citation:

Lowit, A., C C. Dary, F W. Power, J Blancato, R. W. Setzer, R. Conolly, AND M. Seaton. PHYSIOLOGICALLY-BASED PHARMACOKINETICS/PHARMACODYNAMIC MODELING AND CUMULATIVE RISK ASSESSMENT: CASE STUDY FOR THE N-METHYL CARBMATE PESTICIDES. Presented at EPA Science Forum 2004, Washington, DC, June 1-3, 2004.

Impact/Purpose:

Research will be conducted to develop and apply integrated microenvironmental, and physiologically-based pharmacokinetic (PBPK) exposure-dose models and methods (that account for all media, routes, pathways and endpoints). Specific efforts will focus on the following areas:

1) Develop the Exposure Related Dose Estimating Model (ERDEM) System.

Includes: Updating the subsystems and compartments of the ERDEM models with those features needed for modeling chemicals of interest to risk assessors;

Designing and implementing the graphical user interface for added features.

Refining the exposure interface to handle various sources of exposure information;

Providing tools for post processing as well as for uncertainty and variability analyses;

Research on numerical and symbolic mathematical/statistical solution methods and computational algorithms/software for deterministic and stochastic systems analysis.

2) Apply ERDEM and other quantitative models to understand pharmacokinetics (PK) and significantly reduce the uncertainty in the dosimetry of specific compounds of regulatory interest.

Examples of the applications are:

exposure of children to pesticides

study design

route-to-route extrapolation

species extrapolation

experimental data analysis

relationship between parametric uncertainty and the distribution of model results

validity of scaling methods within species

validity of scaling methods from one species to another species

reduction of uncertainty factors for risk assessment

Description:

The Food Quality Protection Act of 1996 [PL 104-170: 110 STAT. 1513] requires EPA to consider potential cumulative human health risks resulting from aggregate exposure to pesticide chemicals acting through a common mechanism of toxicity. This includes all anticipated dietary exposures and all other exposure for which there is reliable information. In 2001, EPA established the N-methyl carbamate pesticides as a common mechanism group based on their structural characteristics and also similarity and shared ability to inhibit acetylcholinesterase (AChE) by carbamylation of the serine hydroxyl group located in the active site of the enzyme. The Office of Pesticide Programs (OPP) expects to release a preliminary cumulative risk assessment for this group in the spring of 2005. OPP is currently evaluating which method or methods will be used to estimate cumulative risk. A collaborative research effort to develop a physiologically-based pharmacokinetic/pharmacodynamic (PBPK/PD) model for the N-methyl carbamate pesticides has been undertaken by the OPP, ORD's National Health and Environmental Effects Laboratory (NHEERL) and National Exposure Research Lab (NERL), and the CIIT Centers for Health Research. PBPK/PD models are very powerful tools that can account for anatomic structure and physiological and biochemical processes. These models can be used to estimate internal exposure dose or concentrations of parent compounds and/or active metabolites at the target site(s) and also toxicologically relevant effects. Typically, inhibition of AChE is fairly rapid (within hours) for members of the N-methyl carbamate common mechanism group. The time dependant relationship between exposure and effect for this group make the N-methyl carbamates a good case study to aid the EPA in developing a multi-chemical, multi-pathway PBPK/PD models for evaluating cumulative risk.

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